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September 12, 2007

Aventis Pharma Deutschland GmbH v. Lupin, Ltd. (Fed. Cir. 2007)

The contours of the Federal Circuit's obviousness jurisprudence post-KSR continued to be revealed today with the CAFC's decision in Aventis Pharma Deutschland GmbH v. Lupin, Ltd. The Federal Circuit reversed a finding in the District Court that the Aventis claims were non-obvious, based on what it termed a "too rigid" application of the CAFC's teaching-suggestion-motivation (TSM) test, which was repudiated by the Supreme Court in KSR Int'l Co. v. Teleflex, Inc.

The case involves Lupin's filing of an Abbreviated New Drug Application (ANDA) for a generic version of the blood pressure medication ramipril (marketed by Aventis' co-plaintiff King Pharmaceuticals, Inc. as Altace®). Ramipril is an angiotensin-converting enzyme (ACE) inhibitor for treating high blood pressure by "inhibit[ing] a biochemical pathway that constricts blood vessels." The District Court found Lupin to be an infringer on summary
judgment under the doctrine of equivalents, and also found after a bench trial that the asserted claims of the patent-in-suit, U.S. Patent No. 5,061,722 were not invalid for obviousness. The pharmaceutical compound Ramipril is one of a plurality of stereoisomers of the chemical compound represented below, where the stereoisomeric conformation of all the chiral carbon atoms designated by an asterisk are in the (S) configuration:

Thus, the pharmaceutical ramipril is one of 32 different stereoisomers; it is known as the "5(S)" or "SSSSS" enantiomer.

Claim 1 of the '722 reads as follows:

1. A compound of the formula

or a physiologically acceptable salt thereof, wherein R2 is hydrogen, methyl, ethyl, or benzyl, and wherein hydrogen atoms on the ring carbon atoms in the 1- and 5-positions are in the cis-configuration relative to one another, the carboxyl group on the ring carbon atom in the 3-position is in the endo position relative to the bicyclic ring system, and the chirality centers in the chain and on the ring carbon atom in the 3-position all have the S-configuration, said compound or salt being substantially free of other isomers.

This claim is limited to the 5(S) enantiomer.

Prior art ACE inhibitors, including a naturally-occurring molecule isolated from snake venom and several synthetic analogues, were structurally similar to ramipril, and importantly had multiple chiral carbon atoms all in the S configuration. The "all S" enantiomer of the most closely-related molecule, enalapril (produced by Merck) had been described as having 700 times the biological activity of the "SSR" stereoisomer; the prior art described how the SSS isomer of enalapril could be separated from the other seven stereoisomeric species of that compound. There was also evidence that a Schering scientist had conceived of the ramipril chemical structure and filed and obtained U.S. patents on her invention. However, these patents do not disclose the active stereochemical conformation of the molecule, and the experimental examples in these patents would be expected to produce less than the complete complement of 32 stereoisomers (perhaps as few as four of them). There was also evidence that the Schering scientist thereafter produced a mixture of the SSSSS and SSSSR enantiomers. All this work occurred prior to Aventis producing ramipril for the first time, but since the 5(S) enantiomer was not known in the prior art, Aventis' claims were novel over this art.

There was one more interesting feature of the factual predicate of the lawsuit. Aventis licensed the Schering patents, and when the Patent and Trademark Office declared an interference between the Schering patents and Aventis' applications, the interference settled. Thus, the invalidity question did not arise during the interference. However, Aventis did concede priority as to the generic ramipril structure, i.e., without specifying the stereochemical configuration of the active ramapril enantiomer.

The District Court found that, on this record, Lupin had failed to present clear and convincing evidence that the patent was invalid for obviousness, but indicated that it was a close case, decided mainly because of the requirement that invalidity be proven by clear and convincing evidence.

The Federal Circuit reversed in a decision by Judge Linn (joined by Judge Mayer and Judge Robertson of the D.C. District Court, sitting by designation). Judge Linn asserted that the prior art contained "a litany of potential prior art references" besides the ones asserted at trial. However, the Federal Circuit focused its analysis on the prior art relating to the Merck compound elanapril, and the Schering invention of the mixture of ramapril stereoisomers, including the mixture of the SSSSS and SSSSR enantiomers. The CAFC noted that the District Court's reasoning in deciding that the claims were not obvious was based primarily on a lack of clear and convincing evidence of any motivation in the art to separate the SSSSS isomer, as required by Aventis' patent claims in suit.

This was error, according to the Federal Circuit. The CAFC cited KSR for the principle that applying the TSM test in a "rigid and mandatory" fashion was erroneous, and for the proposition that it is "necessary to show 'some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness,' but such reasoning 'need not seek out precise teachings directed to the specific subject matter of the challenged claim.'" The Federal Circuit said that requiring an explicit teaching to separate the SSSSS enantiomer as the active species was "precisely the sort of rigid application of the TSM test that was criticized in KSR."

The CAFC focused on the "structural similarity" between the claimed compounds and the prior art. Explicit teaching of a particular utility is not required, the Federal Circuit said, but there must be sufficient structural similarity to show a "sufficiently close relationship" that the skilled worker would expect the new compound to have "similar properties" to the prior art compound(s). And the Federal Circuit's precedents held that structural similarity was enough to establish a prima facie case of obviousness. This analysis extends to mixtures of enantiomers, because the existence of the mixture is not sufficient in every case to render the separated enantiomer non-obvious. For example, the Federal Circuit said a separated enantiomer would be non-obviousness in situations where the existence of a particular enantiomer or its identity as an active ingredient were unknown, or that the art does not teach how to separate the mixture.

However, here the Federal Circuit found ample evidence of invalidity due to obviousness. For example, the CAFC found that the skilled worker would have known how to separate the SSSSS enantiomer of ramipril and would have expected the greater activity results found for the Schering mixture in the prior art. In particular, the Federal Circuit found that the two enantiomers in the Schering mixture, SSSSS and SSSSR, differed at only one position, and that the earlier prior art compounds were all consistent with the "all (S)" enantiomer having the greatest potency. The art, in particular certain of Schering's prior patents, described the SSS configuration as being 700-fold more potent and described how to isolate the 5(S) enantiomer from the other stereoisomers. Moreover, the differences in potency shown for the two enantiomers of elanapril (SSS and SSR) would have lead the skilled worker to expect the activity of ramapril to reside preferentially in the SSSSS enantiomer, due to the close structural similarity between these two molecules. This evidence was enough to convince the Federal Circuit that Aventis' claims were obvious in view of the prior art.

The CAFC also rejected Aventis' argument for unexpected results, and stated that the proper comparator for analyzing whether Aventis' results were unexpected was not all 32 of ramipril's enantiomers but the Schering mixture of the 5(S) and SSSSR enantiomers.

This case is consistent with the results from Pfizer, Inc. v. Apotex, Inc. and Forest Labs., Inc. v. Ivax Pharm., Inc. and indicates that the Federal Circuit's reaction to the Supreme Court's criticism of its jurisprudence in KSR is to emphasize the primacy of structural obviousness in its determinations. The Federal Circuit also appears to be ready to base its decisions on the factual grounds for a non-obviousness determination, where the standard for reversing (clear error) is higher and any judgments are less likely to be invalidated by the Supreme Court.